Dopamine is an important neurotransmitter in the central nervous system (CNS), where it is involved with motor function, perception, cognition, attention, arousal, motivation and emotion. Dopamine imbalance is believed to play a key role in a number of CNS-related disorders such as schizophrenia, Parkinson's disease, drug abuse, eating disorders and depression. Dopamine also has several important roles in the peripheral nervous system, such as in the control of blood to the kidneys and in autonomic ganglion transmission.
Dopamine receptors in the CNS have traditionally been divided into two general categories, designated D-1 and D-2 receptors, based on biochemical and pharmacological differences between the two receptor types. (For a review of the classification and function of dopamine receptor subtypes, see C. Kaiser and T. Jain, "Dopamine Receptors: Functions, Subtypes and Emerging Concepts", Medicinal Research Reviews, 5:145-229, 1985.) Recent molecular biology studies have indicated an even greater heterogeneity of dopamine receptors: the D-2, D-3 and D-4, which are classified as D-2-like, and the D-1 and D-5, which are classified as D-1-like (D. Sibley and F. Monsma, "Molecular Biology of Dopamine receptors", in TIPS, Vol. 13, pp. 61-69, 1992). Attempts to understand the physiological and pathophysiological roles of the various dopamine receptor subtypes are continuing to unveil new avenues for novel therapeutic approaches for the treatment of dopamine-related disorders.
The loss of striatal dopamine within the basal ganglia, the region of the mammalian brain that is involved with motor control, has been established as the fundamental deficit in Parkinson's disease and primary to the etiology of that disease state. This deficiency is addressed via dopamine replacement therapy, primarily with L-DOPA (3,4-dihydroxyphenylalanine), which is converted to dopamine within the brain. L-DOPA has been the cornerstone of Parkinson's disease therapy, and the successes achieved with its therapy have led to the testing of other compounds capable of eliciting the post-synaptic receptor actions of dopamine. Bromocriptine, the most widely used direct-acting dopamine agonist for the treatment of Parkinson's disease, is typically administered adjunctively with L-DOPA in order to lower dosages of the latter required to achieve the desired therapeutic response. Bromocriptine alone has been shown to relieve Parkinson's disease symptoms in some early Parkinson's disease patients, allowing for a delay in the onset of L-DOPA therapy. Chronic L-DOPA use is associated with a number of serious side-effects and limitations, such as the development of dyskinesias, severe response fluctuations (on-off phenomenon) and diminishing efficacy during treatment.
An excess of dopamine in the brain has been identified as the cause of schizophrenia, a psychiatric illness involving disturbance of thought processes, hallucinations and loss of touch with reality. Chronic abuse of stimulants, such as amphetamines, known to enhance dopaminergic activity in the brain, can lead to a paranoid psychosis that is clinically indistinguishable from classic paranoid schizophrenia, further supporting this dopamine theory of schizophrenia.
Anti-schizophrenic drugs are postulated to exert their effects by blocking the dopamine receptors (i.e., acting as receptor antagonists), and consequently preventing excess receptor stimulation (G. P. Reynolds, "Developments in the drug treatment of schizophrenia", in TIPS, 13:116-121, 1992). However, these antipsychotic agents frequently produce undesirable side-effects, the most common of which are the extrapyramidal effects that include bizarre involuntary movements and Parkinson-like states, as well as sedation and hypotension. Because of these often-severe side-effects and the high incidence of patients unresponsive to dopamine blocking drugs, novel and improved therapies continue to be sought.
One complement to dopamine receptor antagonists for the treatment of schizophrenia has included the use of low doses of dopamine agonists, such as apomorphine and bromocriptine (also discussed above), which have been reported to produce antipsychotic effects, possibly due to preferential activation of dopamine presynaptic receptors resulting in decreased dopaminergic activity (M. Del Zompo et al, "Dopamine agonists in the treatment of schizophrenia", Progress in Brain Research, 65:41-48, 1986 and H. Y. Meltzer, "Novel Approaches to the Pharmacology of Schizophrenia", Drug Development Research, 9:23-40, 1986). In addition, the dopamine D1-selective agonist, SKF 38393, when used in conjunction with the antipsychotic drug, haloperidol, a D-2 antagonist, has been shown to ameliorate the undesired side-effects of the haloperidol (M. Davidson, "Effects of the D-1 Agonist SKF-38393 Combined With Haloperidol in Schizophrenic Patients", Arch Gen. Psychiatry, 47:190-191, 1990).
Growing evidence (reviewed by R. A. Wise and P.-P. Rompre in "Brain Dopamine and Reward", Annual Review of Psychology, 40:191-225, 1989) suggests that dopamine also has a central role in the brain's reward system. For example, animals trained to self-administer cocaine will increase their consumption of this drug after treatment with either a D-1 or a D-2 receptor antagonist, presumably in order to maintain the elevated dopamine levels responsible for the drug's euphorigenic and reinforcing properties (D. R. Britton et al, "Evidence for Involvement of Both D1 and D2 Receptors in Maintaining Cocaine Self-Administration", Pharmacology Biochemistry & Behavior, 39:911-915, 1991). The D-1 agonist, SKF 38393, has also been reported to decrease food intake by rats, presumably by direct action of the drug on neural feeding mechanisms. Because of this interrelationship between dopamine and reward, dopaminergic agents would be useful for the treatment of substance abuse and other addictive behavior disorders, including cocaine addiction, nicotine addiction and eating disorders.
Affective disorders, the most common psychiatric disorders in adults, are characterized by changes in mood as the primary clinical manifestation, and result from a reduction in the central nervous system of certain biogenic amine neurotransmitters, such as dopamine, noradrenaline and serotonin. Currently-available antidepressants work primarily by raising biogenic amine neurotransmitter levels, either by inhibiting their uptake or preventing their metabolism. No antidepressant drug to date, however, can substitute for electroconvulsive shock therapy for the treatment of severe, suicidal depression. Currently-available drugs for treating affective disorders unfortunately suffer from delayed onset of action, poor efficacy, anticholinergic effects at therapeutic doses, cardiotoxicity, convulsions and the possibility of overdosing. A large number of clinically-depressed individuals remain refractory to currently available therapies. A role for direct-acting dopamine agonists in antidepressant therapy has been suggested based on the effects observed for several dopamine agonists in various animal models (R. Muscat et al., "Antidepressant-like effects of dopamine agonists in an animal model of depression", Biological Psychiatry, 31:937-946, 1992).
A role for dopamine has also been established in cognition and attention mechanisms. Animal studies support the role of dopamine in attention-related behaviors involving search and exploratory activity, distractibility, response rate, discriminability and the switching of attention. Treatment of cognitive impairment and attention deficit disorders via dopamine-based therapy has been proposed and is under active investigation (F. Levy, "The Dopamine Theory of Attention-Deficit Hyperactivity Disorder (ADHD)", in Australian and New Zealand Journal of Psychiatry, 25:277-283, (1991); T. Sawaguchi and P. S. Goldman-Rakic, "D1-Dopamine Receptors in Prefontral Cortex: Involvement in Working Memory", Science, 252:947-940 (1991); and A. F. T. Arnsten et al., "Dopamine D1 Receptor Mechanisms in the Cognitive Performance of Young Adult and Aged Monkeys", Psychopharmacology, 116:143-151 (1994)).
In addition, dopamine has been identified with a number of effects in the periphery, and has been used in the treatment of shock, congestive heart failure and acute renal failure. Stimulation of the peripheral D-1 receptors causes vasodilation, particularly in the renal and mesenteric vascular beds where large numbers of these receptors are found. The utility of dopamine has been limited, however, by its ability to cause vasoconstriction at higher concentrations, presumably due to its secondary effects on adrenergic receptors, and by its emetic effects due to peripheral D-2 stimulation. Agents selective for the peripheral D-1 receptors appear to offer significant advantages over treatments used currently for these and other related disorders (M. F. Lokhandwala, "Preclinical and Clinical Studies on the Cardiovascular and Renal Effects of Fenoldpam: A DA-1 Receptor Agonist", Drug Development Research, 113:123-124 (1987)).
Also, dopamine in combination with diuretics has been reported to reverse radio-contrast media-induced acute renal failure in patients (Talley et al., Clin. Res., 18:518, 1970), thus suggesting that dopamine agonists may be similarly useful.
A wide variety of structures has been disclosed that are dopamine receptor ligands (H. E. Katerinopoulos and D. I. Schuster, "Structure-Activity Relationships for Dopamine Analogs: A Review", in Drugs Of The Future, Vol. 12, pp. 223-253, 1987) and include the thienopyridines, SKF 86926 (4-(3',4'-dihydroxyphenyl)-4,5,6,7-tetrahydrothieno(2,3-c)-pyridine) and SKF 86915 (7-(3', 4'-dihydroxyphenyl)-4,5,6,7-tetrahydrothieno(3,2-c)-pyridine (P. H. Andersen et al., European Journal of Pharmacology, 137:291-292, 1987; and U.S. Pat. Nos. 4,340,600, to L. M. Brenner and J. R. Wardell, Jr., issued 1982, and 4,282,227, to L. M. Brenner, issued 1981). Nichols et al. have disclosed certain substituted trans-hexahydrobenzo[a]-phenanthridine compounds as dopaminergic ligands (D. E. Nichols and R. R. Mailman, U.S. Pat. No. 5,420,134, issued May 30, 1995; D. E. Nichols, U.S. Pat. No. 5,047,536, issued Sep. 10, 1991; W. K. Brewster et al., Journal of Medicinal Chemistry, 33:1756-1764, 1990; and D. E. Nichols and R. R. Mailman, PCT Application WO9324462, published Dec. 9, 1993).
Although various non-hydroxylated compounds having a fused four-ring system have been disclosed (see, for example, Kiguchi et al., Heterocycles, 19:1873-7, 1982; CA 98:16897, describing various intermediates to ergot alkaloids), it is pertinent to emphasize the structural requirements for dopaminergic activity. C. Kaiser and T. Jain, "Dopamine Receptors: Functions, Subtypes and Emerging Concepts", in Medicinal Research Reviews, Vol. 5, pp. 145-229, 1985), have discussed the structural requirements for dopamine activity and emphasized the important effect thereupon of the placement of hydroxyl groups in candidate compounds.
D. E. Nichols (U.S. Pat. No. 5,047,536, issued Sep. 10, 1991) disclosed that dihydrexidine is active as a dopamine agonist.
Michaelides et al., in PCT application WO94 22858 published Oct. 13, 1994, disclosed tetracyclic compounds of the formula: ##STR3## wherein A and the atoms to which it is attached and the optional double bond represent a mono- or di-heterocyclic ring selected from: ##STR4## wherein X is sulfur or oxygen as having use in the treatment of dopamine-related neurological, psychological and cardiovascular disorders.
Applicants have now discovered that 2,6-, 3,6- and 4,6-diaza-5,6,6a,7,8,12b-hexahydrobenzo[c]phenanthrene compounds are useful agents for the treatment of dopamine-related neurological, psychological and cardiovascular disorders.